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N-ethylmaleimide-sensitive factor (NSF) disassembles fusion-incompetent cis soluble-NSF attachment protein (SNAP) receptor (SNARE) complexes making monomeric SNAREs available for subsequent trans pairing and fusion. In most cells the activity of NSF is constitutive, but in Jurkat cells and sperm, it is repressed by tyrosine phosphorylation; the phosphomimetic mutant NSF-Y83E inhibits secretion in the former. The questions addressed here are if and how the NSF mutant influences the configuration of the SNARE complex. Our model is human sperm, where the initiation of exocytosis (acrosome reaction) de-represses the activity of NSF through protein tyrosine phosphatase 1B (PTP1B)-mediated dephosphorylation. We developed a fluorescence microscopy-based method to show that capacitation increased, and challenging with an acrosome reaction inducer decreased, the number of cells with tyrosine phosphorylated PTP1B substrates in the acrosomal domain. Results from bioinformatic and biochemical approaches using purified recombinant proteins revealed that NSF-Y83E bound PTP1B and thereupon inhibited its catalytic activity. Mutant NSF introduced into streptolysin O-permeabilized sperm impaired cis SNARE complex disassembly, blocking the acrosome reaction; subsequent addition of PTP1B rescued exocytosis. We propose that NSF-Y83E prevents endogenous PTP1B from dephosphorylating sperm NSF, thus maintaining NSF's activity in a repressed mode and the SNARE complex unable to dissociate. The contribution of this paper to the sperm biology field is the detection of PTP1B substrates, one of them likely being NSF, whose tyrosine phosphorylation status varies during capacitation and the acrosome reaction. The contribution of this paper to the membrane traffic field is to have generated direct evidence that explains the dominant-negative role of the phosphomimetic mutant NSF-Y83E.
This article was published in the following journal.
Name: Molecular human reproduction
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SNARE proteins in which the central amino acid residue of the SNARE motif is a GLUTAMINE. They are classified separately from the R-SNARE PROTEINS where the central amino acid residue of the SNARE motif is an ARGININE. Subfamilies, the QA-SNARES; QB-SNARES; and QC-SNARES are grouped by the position of their SNARE motif-containing-domains in the SNARE complex and by their sequence similarities.
A subfamily of Q-SNARE PROTEINS which occupy the same position in the SNARE complex as the C-terminal SNARE domain of SNAP-25 and which also are most similar to the C-terminal region of SNAP-25 in their AMINO ACID SEQUENCE.
A subfamily of Q-SNARE PROTEINS which occupy the same position in the SNARE complex as the N-terminal SNARE domain of SNAP-25 and which also are most similar to the N-terminal region of SNAP-25 in their AMINO ACID SEQUENCE.
A superfamily of small proteins which are involved in the MEMBRANE FUSION events, intracellular protein trafficking and secretory processes. They share a homologous SNARE motif. The SNARE proteins are divided into subfamilies: QA-SNARES; QB-SNARES; QC-SNARES; and R-SNARES. The formation of a SNARE complex (composed of one each of the four different types SNARE domains (Qa, Qb, Qc, and R)) mediates MEMBRANE FUSION. Following membrane fusion SNARE complexes are dissociated by the NSFs (N-ETHYLMALEIMIDE-SENSITIVE FACTORS), in conjunction with SOLUBLE NSF ATTACHMENT PROTEIN, i.e., SNAPs (no relation to SNAP 25.)
SNARE proteins where the central amino acid residue of the SNARE motif is an ARGININE. They are classified separately from the Q-SNARE PROTEINS where the central amino acid residue of the SNARE motif is a GLUTAMINE. This subfamily contains the vesicle associated membrane proteins (VAMPs) based on similarity to the prototype for the R-SNAREs, VAMP2 (synaptobrevin 2).
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